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DGUOK-Related Mitochondrial DNA Depletion Syndrome, Hepatocerebral Form

Synonym: Deoxyguanosine Kinase Deficiency

, MD, , MD, and , PhD.

Author Information
, MD
Department of Molecular and Human Genetics
Baylor College of Medicine
Houston, Texas
, MD
Department of Pediatrics
Medical College of Wisconsin
Milwaukee, Wisconsin
, PhD
Department of Molecular and Human Genetics
Baylor College of Medicine
Houston, Texas

Initial Posting: .

Summary

Disease characteristics. The two forms of deoxyguanosine kinase (DGUOK) deficiency are a hepatocerebral mitochondrial DNA depletion syndrome (multisystem disease in neonates) and isolated hepatic disease later in infancy or childhood. The majority of affected individuals have the multisystem illness with hepatic disease (cholestasis) and neurologic dysfunction evident within weeks of birth. They subsequently manifest severe hypotonia, developmental regression, and typical rotary nystagmus that evolves into opsoclonus. Those with isolated liver disease may also have renal involvement and some later develop mild hypotonia. Progressive hepatic disease is the most common cause of death in both forms.

Diagnosis/testing. Reduced mtDNA copy number in liver or muscle can be used to confirm mtDNA depletion. Molecular genetic testing of DGUOK is necessary to establish the specific diagnosis of DGUOK deficiency.

Management. Treatment of manifestations: Care is best provided by a multidisciplinary team. Children with cholestatic liver disease may require formulas with enriched medium-chain-triglyceride content and fractional meals with enteral nutrition at night for adequate nutrition. Orthotopic liver transplantation provides no survival advantage in children with multisystem illness, but it may be considered in children with isolated liver disease. Appropriate physical therapy could be offered for mild hypotonia observed in persons with isolated liver disease.

Prevention of secondary complications: Avoidance of nutritional deficiencies; adherence to normal immunization schedule.

Surveillance: Routine monitoring of hepatic function, nutritional status, gross motor development and skills, urine for proteinuria and aminoaciduria.

Agents/circumstances to avoid: Sodium valproate; cautious use of isoniazid, acetaminophen, or other medications associated with hepatic dysfunction. Although no data document valproate toxicity specifically in DGUOK deficiency, valproate should be avoided based on the well-known association of valproate use and development of hepatotoxicity in Alpers syndrome, another hepatocerebral syndrome with mtDNA depletion.

Genetic counseling. DGUOK deficiency is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the disease-causing mutations in the family are known.

Diagnosis

Clinical Diagnosis

The diagnosis of deoxyguanosine kinase (DGUOK) deficiency with multisystem disease is suspected in infants with early and progressive liver disease and neurologic features including hypotonia, nystagmus, and psychomotor retardation [Dimmock et al 2008a].

The diagnosis of DGUOK deficiency with isolated hepatic disease later in infancy or childhood is suspected in individuals with progressive intrahepatic cholestasis or virally induced liver failure [Dimmock et al 2008a, Dimmock et al 2008b].

Testing

Newborn screening. Elevated serum concentration of tyrosine or phenylalanine are non-specific abnormalities observed on newborn screening in the majority of infants with the multisystem disease form of DGUOK deficiency diagnosed in the US in the past eight years. Note: (1) Infants with DGUOK deficiency do not excrete succinylacetone in urine, which is diagnostic for tyrosinemia type 1 [Dimmock et al 2008b]. (2) When transient, elevation of serum concentration of tyrosine may be falsely attributed to transient tyrosinemia of the newborn [Lee et al 2009].

Other findings. Findings of intrahepatic cholestasis typically include [Ducluzeau et al 1999, Mandel et al 2001b, Salviati et al 2002, Taanman et al 2002, Taanman et al 2003, Filosto et al 2004, Rabinowitz et al 2004, Labarthe et al 2005, Mancuso et al 2005, Slama et al 2005, Tadiboyina et al 2005, Wang et al 2005, Freisinger et al 2006, Alberio et al 2007, Sarzi et al 2007, Dimmock et al 2008b, Lee et al 2009]:

  • Elevations in serum concentrations of:
    • Alanine aminotransferase (ALT) ranging from normal to 20 times the upper limit of normal (normal: <50 IU/L)
    • Aspartate aminotransferase (AST) ranging from normal to 20 times the upper limit of normal (normal: 45 IU/L)
    • Gammaglutamyltransferase (GGT) ranging from typically normal to twice the upper limit of normal (normal <51 IU/L)
    • Conjugated hyperbilirubinemia ranging from 1.5- to 6-fold the upper limit of normal (normal: < 2 μmol/L); however, in most cases these elevations are typically two- to threefold the upper limit of normal
    • Total bile acids; however, urine FAB-MS profile is not specific for an inborn error of bile acid synthesis
  • Coagulopathy

Serum concentration of alpha fetoprotein (AFP) may or may not be elevated.

Increased serum concentration of ferritin (normal <150 ng/ml), observed in a large number of infants, may be misdiagnosed as neonatal hemochromatosis (see Differential Diagnosis).

Mitochondrial DNA (mtDNA) copy number analysis. Mitochondrial DNA depletion in affected tissues such as liver and muscle can be analyzed by real-time quantitative PCR (qPCR) or oligonucleotide array comparative genomic hybridization (oligo aCGH). Affected liver and muscle demonstrate less than 20% and 40%, respectively, of matched control mtDNA content [Dimmock et al 2008b, Lee et al 2009].

Biochemical Testing

Electron Transport Chain (ETC) activity

Pathology

  • Liver histology typically reveals microvesicular cholestasis, but may show bridging fibrosis, giant cell hepatitis, or cirrhosis. In several individuals the histopathologic picture may be more consistent with neonatal hemochromatosis (see Differential Diagnosis) [Mandel et al 2001a, Labarthe et al 2005, Freisinger et al 2006, Dimmock et al 2008b, Lee et al 2009].
  • Liver electron microscopy may reveal an increase in the number of mitochondria and is commonly associated with abnormal cristae, findings common to all hepatocerebral mtDNA depletion syndromes [Mandel et al 2001a].
  • Skeletal muscle histology is usually normal [Mandel et al 2001b, Labarthe et al 2005, Freisinger et al 2006]; however, multisystem disease may be associated with abnormal muscle histology. In one case, increased mitochondrial accumulation in several fibers with subsarcolemmal accumulation of mitochondria, cytochrome c oxidase-negative ragged red fibers, and lipid accumulation in ragged red fibers were observed [Mancuso et al 2005].
  • Neuropathologic examination may be normal or may reveal focal losses of Purkinje cells with Bergmann gliosis [Filosto et al 2004].

Molecular Genetic Testing

Gene. DGUOK is the only gene mutated in DGUOK deficiency [Mandel et al 2001b].

Testing

  • Sequence analysis of all coding exons and at least 50 bp of flanking intron sequences; mutation detection frequency is currently unknown, but appears to be close to 98% [Author, personal observation].
  • Deletion/duplication analysis
    • Of approximately 50 kindreds studied to date [Dimmock et al 2008b], one was found to have deletion of a single exon of DGUOK [Lee et al 2009]. Oligo aCGH is detects intragenic deletions of DGUOK.
    • Real-time qPCR estimates mitochondrial DNA copy number to rule out mtDNA depletion.
  • Sequence analysis of RNA. Reverse transcription PCR analysis performed on DGUOK RNA extracted from fresh tissue, blood, or skin fibroblast cultures can identify splice-site mutations and abnormally spliced forms [Dimmock et al 2008b; Tang & Wong, unpublished data]. This analysis has been successfully employed in confirming the pathogenicity of splice-site mutations. Note: This method has not been used to detect deep intronic splicing mutations.

Table 1. Summary of Molecular Genetic Testing Used in DGUOK-Related Mitochondrial DNA Depletion Syndrome, Hepatocerebral Form

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
DGUOKSequence analysis 4 of DNASequence variants98%
Deletion/duplication testing 5Exonic or whole-gene deletions2%
Sequence analysis of RNASplice-site mutations and abnormally spliced formsUnknown

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5. Testing that identifies deletions/duplications not detectable by sequence analysis of genomic DNA; includes testing by oligo chromosomal microarray (CMA) and real-time qPCR.

Testing Strategy

To confirm/establish the diagnosis in a proband

  • Multisystem illness
    • Testing of mtDNA copy number in liver or muscle, if available, can be used to confirm mtDNA depletion [Dimmock et al 2008b].
    • If mtDNA depletion is confirmed by real-time qPCR, or if clinical suspicion is warranted without available tissue, sequence analysis should be considered. If sequence analysis does not identify two deleterious mutations, depletion/duplication analysis using oligo CMA should be performed.
    • Note: Testing for ETC deficiencies on skeletal muscle is neither a sensitive nor specific test for DGUOK deficiency.
  • Isolated hepatic disease. Liver biopsy may be necessary to reduce the number of alternative diagnoses under consideration [Suchy 2007] (see Differential Diagnosis). However, in order to avoid an invasive procedure in clinically unstable patients, DNA sequence analysis in blood sample may be considered.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Clinical Description

Natural History

Two forms of deoxyguanosine kinase (DGUOK) deficiency have been observed: multisystem disease in neonates and isolated hepatic disease later in infancy or childhood [Dimmock et al 2008a]. The majority of affected individuals have multisystem illness.

Affected sibs sharing the same mutations have exhibited multisystemic and isolated hepatic disease with divergent long-term outcomes [Tadiboyina et al 2005]. Similarly, diverse long-term outcomes have been observed in affected individuals from unrelated families harboring the same mutations.

Multisystem Illness

Most affected infants have lactic acidosis and hypoglycemia in the first week of life. Within weeks of birth, all infants with this form of disease have hepatic disease and neurologic dysfunction.

Severe myopathy, developmental regression, and typical rotary nystagmus developing into opsoclonus are also seen. In particular, nystagmus and opsoclonus are associated with poor long-term outcome.

Cholestasis is prominent early in the clinical course [Dimmock et al 2008a]. Liver involvement may cause neonatal- or infantile-onset liver failure. The liver failure is generally progressive with ascites, edema, and hemorrhage due to decrease of clotting factors. However, in one affected individual, hepatic dysfunction reversed and currently this individual continues to thrive with supportive care [Mousson de Camaret et al 2007].

Isolated Hepatic Disease

A minority of currently described affected individuals initially presents in infancy or childhood with isolated hepatic disease, occasionally following a viral illness.

Some of these individuals may also have renal involvement manifest as proteinuria and aminoaciduria. No correlation is observed between the presence of this renal tubulopathy and long-term outcome [Dimmock et al 2008a].

Long-term follow-up suggests that these individuals may subsequently develop mild hypotonia but otherwise have a good outcome without severe neurologic involvement [Dimmock et al 2008a].

Viral infections, such as herpes simplex infection, have been associated with acute hepatic decompensation in one kindred with isolated hepatic disease [Dimmock et al 2008b].

Findings Common to Both Forms

Hepatic dysfunction is progressive in the majority of individuals with both forms of DGUOK deficiency and is the most common cause of death. However, hepatic disease has undergone reversal in one individual with isolated liver disease [Mousson de Camaret et al 2007].

One individual with isolated liver disease subsequently developed hepatocellular carcinoma. An abdominal mass was detected in another person with multisystemic disease prior to death [Dimmock et al 2008a].

Findings Not Observed

Findings common to other forms of mtDNA depletion that are not observed in DGUOK deficiency include cardiac dysfunction or arrhythmias; seizures; elevated serum CK concentration; or abnormalities on brain imaging [Dimmock et al 2008b].

Genotype-Phenotype Correlations

No clear genotype/phenotype correlation is evident among individuals with missense mutations.

Affected sibs with the same missense mutations have exhibited divergent long-term outcomes [Tadiboyina et al 2005]. Similarly, diverse long-term outcomes have been observed in affected individuals from unrelated families harboring the same missense mutations.

These findings suggest that in individuals with missense mutations, the genotype and/or family history may not be helpful in predicting long-term outcome or guiding therapeutic decisions [Dimmock et al 2008a].

In contrast, to date, all individuals with two null mutations have had multisystem disease and a more severe clinical phenotype [Dimmock et al 2008a].

Penetrance

The penetrance is estimated to be 100%, but with significant variability in the phenotype [Dimmock et al 2008a].

Prevalence

No large population-based studies have evaluated the prevalence of mtDNA depletion in general or DGUOK deficiency specifically. To the Authors’ knowledge, to date approximately 100 persons with DGUOK deficiency have had a confirmed molecular diagnosis [Dimmock et al 2008a; Wong, unpublished data].

Differential Diagnosis

Multisystem Illness

Mitochondrial DNA depletion is a significant cause of mitochondrial disease. Several other genes including MPV17, POLG, TWINKLE (C10orf2), and RRM2B are also responsible for mtDNA depletion associated with hepatoencephalopathy and may be clinically indistinguishable from deoxyguanosine kinase (DGUOK) deficiency at the time of presentation [Dimmock et al 2008b]. In contrast to Alpers syndrome caused by POLG mutations, DGUOK deficiency is not characterized by seizures or brain-imaging abnormalities [Dimmock et al 2008b].

In one recent study in which 50 of 100 children with multiple electron transport chain defects had a mtDNA copy number less than 35% of normal controls, 18% of those with mtDNA depletion had DGUOK mutations and 18% had POLG mutations. Among those with mtDNA depletion and hepatic dysfunction, DGUOK deficiency was the most common single cause [Sarzi et al 2007].

Mutations in the complex III subunit assembly gene, BCS1L, are associated with significant hepatic dysfunction with significant cognitive impairment and renal tubulopathy.

Hepatic failure and severe encephalopathy have also been associated with compound heterozygosity for two mutations in SCO1.

A significant proportion of neonates with DGUOK deficiency have findings that overlap with neonatal hemochromatosis, in which salivary gland biopsy shows iron granules within the salivary gland epithelium [Smith et al 2004, Labarthe et al 2005, Dimmock et al 2008b].

Isolated Hepatic Disease

The primary differential diagnosis of hepatic mtDNA depletion involves other age-specific causes of cholestatic liver diseases, including:

For a more comprehensive review, readers are referred to Dr. Suchy’s introductory chapter in Liver Disease in Children [Suchy 2007].

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with deoxyguanosine kinase (DGUOK) deficiency, the following are recommended:

  • Evaluation of hepatic status by a physician familiar with the care of children with liver failure. Initial testing should include measurement of serum concentrations of AST, ALT, GGT, albumin and prealbumin, and coagulation profile (including PT and PTT).
  • AFP is a sensitive, but not specific, marker used to differentiate hepatocellular carcinoma from nonmalignant liver disease. Although the value of a highly elevated serum concentration of AFP in the detection of hepatocellular carcinoma in DGUOK deficiency is not known, the possibility of hepatocellular carcinoma should be considered in individuals with a solid tumor detected by abdominal ultrasound examination and a highly increased serum AFP concentration [Freisinger et al 2006].

    Note: Liver biopsy, if required for diagnosis, also allows for staging of the liver disease; however, it confers considerable risk and may not assist significantly in management.
  • Nutritional assessment by a dietician with experience in managing children with hepatic failure
  • Urine analysis and evaluation for urine amino acids

Treatment of Manifestations

Management requires a multidisciplinary team.

Management of liver disease should be guided by the results of initial evaluation in consultation with a hepatologist.

Children with cholestatic liver disease or renal disease are at significant risk of nutritional insufficiency [Feranchak & Sokol 2007]; therefore, a dietician with experience in managing children with hepatic and renal failure should be involved in their care.

  • Formulas with an enriched medium-chain-triglyceride content may provide better nutritional support for infants with cholestasis than formulas with predominantly long-chain triglycerides [Feranchak & Sokol 2007].
  • Cornstarch may reduce symptomatic hypoglycemia in individuals with isolated hepatic disease [Dimmock et al 2008b].
  • Fractional meals and enteral nutrition during the night can result in good nutritional control [Ducluzeau et al 2002].

Orthotopic liver transplantation

  • For children with multisystem illness, orthotopic liver transplantation provides no survival benefit [Dimmock et al 2008a].
  • Several children with isolated hepatic or hepatorenal disease have had excellent ten-year survival with orthotopic liver transplantation and, thus, it is a potential therapeutic option. However, this option warrants discussion with parents: at least one child with isolated liver disease developed neurologic features after liver transplantation [Dimmock et al 2008a].
  • Beyond the issues surrounding hepatic dysfunction, liver transplantation may be indicated in this disease because of the potential for malignant transformation to hepatocellular carcinoma [Dimmock et al 2008b]; however, there are no clear data on the long-term risks for development of hepatocellular carcinoma in transplanted liver.
  • The decision regarding orthotopic liver transplantation must be weighed against the known long-term risks of liver transplantation.

Even in long-term survivors, hypotonia may be significant. Therefore, ongoing monitoring of gross motor development and skills with the intervention of appropriate therapies is appropriate in these children.

Although it is used in other cholestatic disorders [Feranchak & Sokol 2007], ursodeoxycholic acid has no proven efficacy in this disease. The one infant with multisystemic disease did not benefit from treatment with this medication [Lee et al 2009].

Prevention of Secondary Complications

Nutritional deficiencies such as essential fatty acid deficiency and fat-soluble vitamin deficiency need to be prevented. Specific management requires a dietician experienced in the management of individuals with liver disease. Affected individuals need to be supplemented with fat-soluble vitamins and essential fatty acids. Further specific strategies are discussed by Feranchak & Sokol [2007].

Because routine immunizations have not been associated with clinical decompensation in persons with DGUOK deficiency, routine immunizations, including influenza vaccine, are recommended at this time for all individuals with DGUOK deficiency and their household contacts.

Surveillance

Routine monitoring for [Feranchak & Sokol 2007, Dimmock et al 2008a]:

  • Hepatic function
  • Nutritional status
  • Evidence of myopathy
  • Gross motor development and skills
  • Evidence of renal disease (proteinuria and aminoaciduria)

Although monitoring for hepatocellular carcinoma is warranted, no surveillance protocol has been established.

Agents/Circumstances to Avoid

Although persons with DGUOK deficiency do not appear to develop seizures and thus are not typically treated with sodium valproate, it is prudent not to use sodium valproate as it is associated with hepatic decompensation in mitochondrial DNA depletion syndromes [Delarue et al 2000, Kayihan et al 2000, McFarland et al 2008, Uusimaa et al 2008].

No studies exist evaluating the safety of isoniazid, acetaminophen, or other medications normally associated with hepatic dysfunction in this disorder. Their use should be considered on a case-by-case basis.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

To date there are no randomized controlled trials of therapy in this disorder [Dimmock et al 2008a].

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Deoxyguanosine kinase (DGUOK) deficiency is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes and therefore carry one mutant allele.
  • Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be clinically unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. The offspring of an individual with DGUOK deficiency would be obligate heterozygotes (carriers) for a disease-causing mutation in DGUOK. However, to date no affected individuals have reproduced; therefore, fertility is not yet known.

Other family members of a proband. Each sib of the proband’s parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing of at-risk family members is possible if the disease-causing mutations have been identified in the family.

For unrelated reproductive partners of carriers, molecular genetic testing by sequencing of the coding exons and at least 50 bp of the flanking intronic regions of DGUOK is possible.

Related Genetic Counseling Issues

Although penetrance of DGUOK deficiency is probably complete, age of onset and severity of the clinical symptoms vary, even in the same family.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Molecular genetic testing. If the disease-causing mutations have been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villous sampling (usually performed at ~10-12 weeks’ gestation). Molecular genetic analysis of the known familial mutations is the preferred method for prenatal diagnosis [Dimmock et al 2008b].

Although molecular prenatal testing is possible, extreme caution should be exercised in counseling as not all individuals with two DGUOK mutations will experience multisystemic disease and, in addition, no clear genotype-phenotype correlation is observed among individuals with missense mutations. Molecular genetic testing can determine whether or not a fetus has inherited the DGUOK mutations; however, it cannot predict the appearance or severity of clinical manifestations as findings vary even within the same family.

Preimplantation genetic diagnosis (PGD) may be an option for families in which the disease-causing mutations have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • American Liver Foundation
    75 Maiden Lane
    Suite 603
    New York NY 10038
    Phone: 800-465-4837 (Toll-free HelpLine); 212-668-1000
    Fax: 212-483-8179
    Email: info@liverfoundation.org
  • Canadian Liver Foundation (CLF)
    2235 Sheppard Avenue East
    Suite 1500
    Toronto Ontario M2J 5B5
    Canada
    Phone: 800-563-5483 (toll-free); 416-491-3353
    Fax: 416-491-4952
    Email: clf@liver.ca
  • Childhood Liver Disease Research and Education Network (ChiLDREN)
    The Children's Hospital, Section of Pediatric Gastroenterology/Hepatology/Nutrition
    13123 East 16th Avenue
    Suite B290
    Aurora CO 80045
    Phone: 720-777-2598
    Fax: 720-777-7351
    Email: hines.joan@tchden.org
  • Children's European Mitochondrial Disease Network
    Mayfield House
    30 Heber Walk
    Northwich CW9 5JB
    United Kingdom
    Phone: +44(0) 01606 43946 (Helpline)
    Email: info@cmdn.org.uk
  • Children's Liver Disease Foundation (CLDF)
    36 Great Charles Street
    Birmingham B3 3JY
    United Kingdom
    Phone: +44 (0) 121 212 3839
    Fax: +44 (0) 121 212 4300
    Email: info@childliverdisease.org
  • United Mitochondrial Disease Foundation (UMDF)
    8085 Saltsburg Road
    Suite 201
    Pittsburg PA 15239
    Phone: 888-317-8633 (toll-free); 412-793-8077
    Fax: 412-793-6477
    Email: info@umdf.org
  • RDCRN Patient Contact Registry: North American Mitochondrial Disease Consortium

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. DGUOK-Related Mitochondrial DNA Depletion Syndrome, Hepatocerebral Form: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
DGUOK2p13​.1Deoxyguanosine kinase, mitochondrialDGUOK databaseDGUOK

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for DGUOK-Related Mitochondrial DNA Depletion Syndrome, Hepatocerebral Form (View All in OMIM)

251880MITOCHONDRIAL DNA DEPLETION SYNDROME 3 (HEPATOCEREBRAL TYPE); MTDPS3
601465DEOXYGUANOSINE KINASE; DGUOK

Gene structure. The gene is approximately 33 kb in size and consists of seven coding exons. The cDNA is approximately 1.3 kb. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. There are no common mutations or mutation hot spots [Dimmock et al 2008b].

Normal gene product. Deoxyguanosine kinase (DGUOK) is a mitochondrial protein that has a molecular weight of 28 kd with 277 amino acids.

Abnormal gene product. Missense, nonsense, and splice-site mutations result in a reduction or absence of DGUOK enzyme activity. This reduced enzyme activity causes an imbalance of the mitochondrial deoxynucleotide pools. Because the mitochondria depend heavily on the salvage pathway for the supply of deoxynucleotides, DGUOK deficiency results in mitochondrial DNA depletion [Ashley et al 2007].

References

Literature Cited

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  2. Arnér ES, Spasokoukotskaja T, Eriksson S. Selective assays for thymidine kinase 1 and 2 and deoxycytidine kinase and their activities in extracts from human cells and tissues. Biochem Biophys Res Commun. 1992;188:712–8. [PubMed: 1359886]
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Chapter Notes

Revision History

  • 18 June 2009 (et) Review posted live
  • 10 February 2009 (fs) Original submission
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